Ultrasonographic measurements of the hepatobiliary axis of children with sickle cell anaemia in steady state

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1 Ultrasonographic measurements of the hepatobiliary axis of children with sickle cell anaemia in steady state 1 EN Ngige, 2 JK Renner, 2 EO Temiye, 3 OF Njokanma, 4 RA Arogundade, 5 AN David 1 Anambra State Government House, Awka 2 Department of Paediatrics, Lagos University Teaching Hospital, Lagos 3 Havana Specialist Hospital, Lagos 4 Department of Radiology, Lagos University Teaching Hospital, Lagos 5 R-Jolad Hospital, Lagos Correspondence Dr. Fidelis Njokanma Havana Specialist Hospital, Lagos 115 Akerele Extension, Suru-Lere, Lagos faconj@yahoo.com Key words: hepatobiliary axis, ultrasonography, sickle cell anaemia, children, steady state SUMMARY Sickle cell anaemia is associated with structural manifestations in the hepatobiliary axis but these manifestations have not been sufficiently examined in Nigerian or African children. This study was conducted to evaluate the results of ultrasono-graphic measurements of the hepatobiliary axis of children with sickle cell anaemia in a Nigerian teaching hospital. One hundred and twenty children with Hb SS in steady state aged between 12 months and 15 years and sixty children with Hb AA matched by age and sex (as controls) were consecutively recruited from April through November Past and present medical histories were obtained and physical examination and abdominal ultrasonography were performed. The mean liver span, the common hepatic duct and common bile duct diameters, the longitudinal and transverse dimensions (but not the wall thickness) of the gallbladder were significantly higher in test subjects than controls (p< 0.05). Multiple regression showed that age correlated significantly with all the studied ultrasound scan (USS) measurements (p< 0.05). Recurrent episodes of abdominal pain correlated with gallbladder wall thickness (p = ). Number of episodes of jaundice also correlated significantly with bile duct diameter (p=0.003). There were no sex differences in all the parameters measured. Blood transfusions had no significant association with the measured ultrasound parameters. A need for paediatric standards for hepatobiliary ultrasonographic measurements is underscored by the documentation of age as a strong independent predictor. The strong correlation between frequent abdominal pain and increased thickness of the gallbladder, raises the possibility that some of the episodes of abdominal pain may have been due to cholecystitis. INTRODUCTION The liver and biliary tracts are often involved in the pathological processes inherent in sickle cell anaemia. 1 These include long-standing severe anaemia, prolonged and repeated haemolytic processes with increased excretion of bilirubin and deposition of pigments, repeated transfusions leading to exogenous haemochromatosis, stagnation of sickled red cells in the hepatic sinusoids with sinusoidal obstruction, vascular occlusion by agglutinative thrombi 2 and infections, especially viral hepatitis. It may therefore be reasonably expected that some structural and functional derangement of the hepatobiliary axis 44 Volume 1 Number

2 would occur in persons with sickle cell anaemia. Indeed, hepatomegaly has been described as one of the most constant findings in sickle cell anaemia 3 and its persistence as an index of severity of disease. 4 Studies carried out on the hepatobiliary system of Nigerians who have sickle cell anaemia have often dwelt more on functional derangements. 5 Thus, results of studies which evaluate liver enzymes and serum bilirubin are fairly readily available. 5,6 There is, however, a gap in the knowledge of the structural changes associated with sickle cell anaemia. Extremely few studies have investigated, by actual measurements, changes or otherwise occurring in the liver, the gallbladder and/or related ducts. The few available ones concentrated more on the extrahepatic biliary tract 7,8,9 to the exclusion of liver substance. Thus, potentially valuable information that might have been provided by hepatic ultrasonography remains largely untapped. Ultrasonography provides reliable and reproducible results. It is safe, non-invasive, and now relatively cheap and widely available. There is no risk associated with repeated investigation and it can be freely used for follow-up studies. It is, therefore, an ideal means of investigating the hepatobiliary axis. The aim of this study is to document the ultrasonographic findings of the liver, gallbladder and related ducts of sickle cell anemia patients in steady state, attending the paediatric sickle cell clinic of the Lagos University Teaching Hospital. SUBJECTS AND METHODS The study was carried out in the Lagos University Teaching Hospital (LUTH), a tertiary health facility in Nigeria s former capital city. The hospital caters for a sizeable number of patients with sickle cell anaemia and has a specialist clinic for children with this condition. The clinic operates once a week with an attendance of about 40 children per session. A prospective study was conducted from April through November Approval was obtained from the Ethical Committee of LUTH. The primary subjects were 120 children recruited consecutively, who had to satisfy the following criteria: age between 12 months and 15 years; genotype Hb SS; steady state, ie, apparently well (subjectively and objectively), without evidence of recent (4 weeks) infection, crises or other problems. 10 Following identification, written informed consent was obtained from the parent or guardian and a pretested questionnaire was administered. The questionnaire sought details of the past and present medical histories of the child. Older children who came unaccompanied were requested to respond directly to the questionnaire. A thorough physical examination was conducted and the patient was scheduled for ultrasonographic abdominal examination at the radiology department of the hospital. The secondary subjects (control group) were sixty children in good health with genotype Hb AA matched for age and sex with the primary subjects. They were attending the Well Baby/Child Clinic and the general Paediatric Out Patient Clinic for routine follow-up after being managed in the distant past for non-hepatic and non-haematologic illnesses. The health status of the control group was determined by exclusion of symptoms and signs of ill health using a questionnaire, hospital records and a thorough clinical examination. Potential controls were excluded if there was a recent (4 weeks) acute illness or history suggestive of chronic illness, a history of post-neonatal jaundice or liver disease or prior blood transfusion. Each control also had an abdominal ultrasonographic examination. ** ULTRASONOGRAPHY The older subjects and members of the control group were asked to fast overnight before the study, while the younger ones aged 7 years and below were required to fast for 4 hours prior to the ultrasound scan. This was to ensure adequate distension of the gallbladder for excellent cystic landmarks. Patients were made to lie supine. Coupling ultrasonography gel was applied over the right upper quadrant and epigastric regions of the abdomen and the transducer was placed over the same area and manoeuvred until the structures were identified in either oblique or supine positions of the transducer. Structures searched for were the liver (for its span), the gallbladder, the common hepatic and common bile ducts. The liver area was scanned in multiple planes (saggital, transverse and oblique). The liver span was taken as the liver length measured at the level of the midclavicular line. ** A Siemens Sonoline Ultrasound Scanner with 3.5 megahertz sector transducer was used. Volume 1 Number

3 Architecture and echogenicity of the liver were determined in comparison to the right kidney. Measurements taken were the maximum length of the gallbladder, the transverse diameter of the gallbladder, the wall thickness (measured from the anterior wall) of the gallbladder, the common hepatic duct and the common bile duct diameters. All measurements were made intraluminally in millimeters. DATA ANALYSIS The records were entered into an IBM compatible computer system by two independent clerks to facilitate discovery of discrepant entries. Data were analysed using the Microsoft Excel statistical package enhanced by Megastat software. The mean, standard deviation and other appropriate descriptive statistical values were determined for continuous variables. Comparisons of ultrasono-graphic and other findings were made between the subjects and the control group. Intragroup comparisons within the subject group were made to test the role of certain factors like age and frequency of illness. Statistical significance was assessed using student t-test, chi-square (P 2 ) tests and correlation analysis where applicable. Probability values less than 0.05 were accepted as statistically significant. RESULTS A total of 180 children were recruited into the study. Of this number, 120 were test subjects confirmed to have genotype HbSS by haemoglobin electro-phoresis. They were in steady state. The control group consisted of 60 children with genotype HbAA; they were age and sex matched to the subjects (thus a subject-control ratio of 2:1). There were 64 males and 56 female test subjects with mean age of 6.86 years (+ 3.92). The distribution was similar to that of the control group: 32 males and 28 females with mean age 6.95 years (+ 3.94). The liver architecture (echogenicity) of all the subjects and members of the control group were normal and no intrahepatic calculi were observed in any of them. Other findings were: three gallbladders with irregular shapes (two among sickle cell anaemia patients and one in a control), two curved gallbladders (one each in the subject and control groups), one bi-lobed gallbladder and one intraluminal gallbladder septa (both in sickle cell anaemia subjects). All these are normal variants. Table 1 compares hepatobiliary ultrasono-graphic measurements between the subjects and the control group. The mean liver span, common hepatic duct diameter, common bile duct diameter, longitudinal and transverse dimensions of the gallbladder were all significantly higher in the test subjects than in the control group (p< 0.05). The gallbladder wall thickness was slightly higher in the control group, but this was not statistically significant (p = 0.2). Table 2a shows the mean ultrasonographic measurements in test subjects grouped according to age. The analysis of variance (ANOVA) (table 2b) showed a significant, age-related increase in the values of the various ultrasound parameters. Table 3 shows the mean ultrasonographic measure-ments with respect to the number of episodes of abdominal pain in the 6-month period preceding the study. Multiple episodes of abdominal pain were associated with significantly higher gallbladder wall thickness (p <0.01) and wider common bile ducts (p<0.02). With respect to number of blood transfusions in the 12-month period prior to the study, there was no significant difference between those who received no transfusions and those who received two or more transfusions (p > 0.05 in all cases). Table 1. Comparison of ultrasonographic measurements between subjects and controls Variable (mm) (n=120) (n=60) t-test p value 46 Volume 1 Number

4 Liver span (20.75) (14.75) 10.1 < Common hepatic duct 1.89 (0.43) 1.56 (0.43) Gallbladder (length) (10.53) (13.90) Gallbladder (transverse) (6.90) (4.19) 3.84 < Gallbladder wall thickness 1.66 (0.77) 1.78 (0.47) Common bile duct 2.35 (0.48) 1.74 (0.42) 8.75 < Figures in brackets are one standard deviation of the mean. mm = millimetre Table 2a. Mean ultrasonographic measurements in millimetres with respect to age of subjects Age of subjects (yrs) 1-3 (n=27) 4-6 (n=40) 7-9 (n=20) (n=19) (n=14) Variable (mm) Liver span (15.5) (10.88) (15.17) (15.62) (16.3) Hepatic duct diameter 1.70 (0.39) 1.84 (0.29) 2.06 (0.57) 2.04 (0.48) 1.95 (0.39) Gall bladder (length) 50.6 (11.11) 48.6 (6.46) 51.5 (7.96) 57.9 (12.43) 64.5 (9.16) Gall bladder (transverse) 16.1 (8.27) 15.9 (5.06) 18.5 (5.37) 18.2 (6.78) 22.1 (8.94) Gall bladder (wall thickness) 1.23 (0.57) 1.69 (0.78) 1.70 (0.77) 1.97 (0.75) 2.36 (0.68) Bile duct diameter 1.93 (0.32) 2.33 (0.32) 2.55 (0.39) 2.70 (0.47) 2.42 (0.33) Figures in brackets are one standard deviation of the mean. mm = millimetre.yrs = years Table 2b. Analysis of variance of ultrasound measurements according to age Parameter F-statistic p Value Liver span Hepatic duct diameter Gall bladder (length) 9.72 Gall bladder (transverse) Gall bladder (wall thickness) Bile duct diameter Table 3. Mean ultrasonographic measurements with respect to number of episodes of abdominal pain No. of episodes of abdominal pain. 0 1 or 2 $3 t-test p-value n = 58 n =34 n = 28 Parameter Liver span (22.60) (19.4) (17.34) 0.52 >0.5 Hepatic duct diameter 1.84 (0.34) 1.84 (0.37) 2.05 (0.6) 1.72 >0.05 Gall bladder length 53.3 (10.65) 50.9 (11.75) 54.3 (8.58) 0.47 >0.5 Gallbladder (transverse) 17.3 (6.88) 16.7 (6.80) 18.8 (7.15) 0.92 >0.2 Gallbladder (wall thickness) 1.45 (0.67) 1.67 (0.71) 2.10 (0.88) 3.45 <0.01 Bile duct diameter 2.27 (0.48) 2.29 (0.34) 2.59 (0.54) 2.67 <0.02 Volume 1 Number

5 Figures in brackets are one standard deviation of the mean; mm = millimetre; t-test was between those with no episodes of abdominal pain and those with 3 or more episodes Table 4. Univariate correlation between ultrasonographic measurements and age in subjects and controls Parameter Correlation coefficient t-test p-value Liver span Common hepatic duct diameter Gallbladder length Gallbladder transverse diameter Gallbladder wall thickness Common bile duct diameter Table 5. Summary of multiple correlation analysis between ultrasonographic measurements and selected potential independent variables Dependent Variables R 2 F-statistic p-value Liver span Common hepatic duct diameter Gallbladder length Gallbladder transverse diameter Gallbladder wall thickness Common bile duct diameter Note: Independent variables were age, gender, number of blood transfusions, number of episodes of jaundice and number of episodes of abdominal pain; R 2 = coefficient of multiple determination. CORRELATION ANALYSIS Results of univariate analysis between age and ultrasonographic measurements in subjects are shown in table 4. Strong positive correlations were found with respect to all tested parameters both in the subjects and the controls. Multiple regression models were set up to study the relative contributions of selected potential explanatory variables to the changes observed in ultrasonographic parameters. The selected factors were age, gender, number of blood transfusions, number of episodes of jaundice and number of episodes of abdominal pain. There was significant multiple correlation between the individual ultrasonographic features and the selected factors (table 5). The number of episodes of abdominal pain contributed significantly to variations in the gallbladder wall thickness (t = 3.90, p = ) and the transverse diameter of the gallbladder (t = 48 Volume 1 Number

6 3.51, p = ). With respect to the diameter of common bile duct diameter, the number of episodes of jaundice was also significant (t = 3.70, p = 0.003). Gender and number of blood transfusions within the previous year did not contribute significantly to variations in any of the measured parameters. DISCUSSION Ultrasonographic examination of sickle cell anaemia patients in steady state afforded the opportunity to evaluate the baseline features of the subjects in their best state of health. This is because the direct effects of an acute illness would be expected to have been resolved within the 4-week interval of apparent good health. Thus, departures from the normal can be accepted as reflecting the intrinsic consequences of the disorder itself, or its chronic manifestations. It was observed in the study that for all the parameters measured (except gallbladder wall thickness), values were higher in the subjects than in the controls. This is understandable, considering the fact that the hepatobiliary system tends to be overworked in sickle cell anaemia as a result of the high turnover rate of red blood cells presented to the reticuloendothelial system for lysis. Other studies done elsewhere at different times have recorded similar results. 7,11,12 The age of subjects played a very prominent role in the ultrasonographic measurements herein recorded. The mean values of all studied parameters demonstrated a clear positive age-related trend, confirmed both in univariate and in multiple correlation models. Indeed, age was the only predictor variable that consistently showed significant partial correlation in all multiple correlation models. This underscores the need for the establishment of normal age-sensitive standards for the ultrasonographic evaluation of the hepato-biliary system in children. An attempt to compare results was frustrated by nonavailability of relevant studies. With the possible exception of gallbladder wall thickness, the definition of abnormal measure-ments involving the hepatobiliary axis of paediatric subjects has received very little attention. Indeed, the fairly uniform agreement to use 3mm as the upper limit of normal for gallbladder wall thickness also applies to adults. Review of available published clinical studies and standard texts on ultrasonography failed to yield other paediatric standards for comparison. Many studies opted for comparing findings with adult values, possibly because the subjects were a mixture of children and adults. 12,15,16 Such an approach would clearly have been inappropriate for the current study with only paediatric subjects, more so as it was found that most measurements were age-related. Using the reference figure of 3mm as cut-off point, 8.3% of subjects had thickened gallbladder wall, a result almost identical to the 8.1% reported in Ilorin 7 but higher than 3.7% reported in India. 12 The mean gallbladder wall thickness increased significantly with multiple episodes of abdominal pain. This was corroborated in the multiple regression model in which the number of episodes of abdominal pain was a significant independent determinant of gallbladder wall thickness. It is known that increased gallbladder wall thickness may be a non-specific finding. 19 However, in adults as well as children, an increase in thickness may accompany both acute and chronic cholecystitis, conditions to which patients of sickle cell anaemia are prone. It is therefore attractive to suggest that at least some of the episodes of abdominal pain in study patients with thickened gallbladder walls may have been due to cholecystitis. The study indicates that in the ultrasonographic evaluation of the gallbladder, measurement of wall thickness is of more value than longitudinal or transverse dimensions: these dimensions did not show significant association with any of the pathological processes studied. The gallbladder is known to exhibit much variability in shape, which may very likely affect the results of diametric measurements. This variability in shape is one reason gallbladder wall thickness is regarded as a more reliable index of disease. 19 In the multiple regressive models, the number of blood transfusions and the number of episodes of jaundice did not show significant correlation with ultrasound measurements obtained. The number of episodes of abdominal pain was only significantly contributory to gallbladder wall thickness. The reason for the lack of correlation is probably because the subjects were studied in steady state. Thus the effects of variables such as blood transfusion and jaundice may have worn off by the time of the study. CONCLUSION In conclusion, it is pertinent to note that age is a strong independent predictor of hepatobiliary measurements. There is, therefore, a need for the development of Volume 1 Number

7 paediatric standards for comparison. Steady state sickle cell anaemia was associated with relatively high dimensions of almost all parameters studied. In addition, frequent abdominal pain correlated strongly with increased thickness of the gallbladder, raising the possibility that some of the episodes of abdominal pain may have been due to cholecystitis. REFERENCES 1. Johnson C. (2001). Gallbladder and liver disorders in sickle cell disease: A critical review: edu/liver,html. 2. Holkovitz G, Jacobson A. Hepatic dysfuction and abnormalities of the serum protein and serum enzymes in sickle cell anaemia. J Lab Clinic Med. 1961; 57: Bauer TW, Moore GW, Hutchins GM. The liver in sickle cell disease: A clinico-pathological study of 70 patients. Am J Med. 1980; 69: Olatunji PO, Falusi AG. Persistent hepatomegaly: an index of severity in sickle cell anaemia. East Afr Med J 1994; 71: Ojuawo A, Adedoyin MA, Fagbule D. Hepatic function tests in children with sickle cell anaemia during vasoocclusive crisis. Cent Afr J Med 1994; 40: Kaine WN, Udeozor IO. Sickle cell hepatic crisis in Nigerian children. J Trop Paediatr. 1988; 34: Nzeh DA, Adedoyin MA. Sonographic pattern of gallbladder disease in children with sickle cell anaemia. Paediatr Radiol. 1989; Ali AF, Lewis EA. The liver in sickle cell anemia. Ghana Med J. 1969; 8: Okhuonghae HO, Szlechatka R, Sagay AS. Cholelithiasis in children with homozygous sickle cell anaemia in Northern Nigeria. Trop Geogr Med. 1993; 45: Adekile AO, Adeodu AA, Jeje AA, Odesanmi WO. Persistent gross splenomegaly in Nigerian patients with SCA: Relationship to malaria. Ann Trop Paediatr. 1988; Walker TM, Serjeant GR. Billary sludge in sickle-cell disease. J Pediatr. 1996; 129: Tripathy D, Drash BP, Mohaptra BN Kar BC. Cholelithiasis in SCD in India. J Assoc Physicians India 1997; 45: Lang FC, Ferderle MP, Jeffery RB, Brown TW. Ultrasonic evaluation of patients with acute right upper quadrant pain. Radiol. 1981; 140: Arnon S, Rosenquist CJ. Gray scale cholecystography: an evaluation of accuracy. Am J Radiol. 1976; 127: Gosink BB, Ley Master CE. Ultrasonic determination of hepatomegaly J Clin Ultrasound. 1981; 9: Wolson AH. Liver. In: Goldberg BB, Kurtz AB, editors,. Atlas of Ultrasound Measurements. Chicago: Year Book Medical Publishers; Durie PR. The liver. In: Stringer DA, editor, Pediatric Gastrointestinal Imaging. Hamilton, Ontario: BC Decker; Holmes JH, Sundgren C, Ikle D et al. A simple ultrasonic method for evaluating liver size. J Clin Ultrasound. 1977; 5: McGahan JP, Phillips AE, Cox KL. Sonography of the normal pediatric gallbladder and biliary tract. Radiol.1982; 144: Volume 1 Number